Early 7,8-Dihydroxyflavone Administration Ameliorates Synaptic and Behavioral Deficits in the Young FXS Animal Model by Acting on BDNF-TrkB Pathway.

Fragile X syndrome (FXS) is the leading inherited form of intellectual disability and the most common cause of autism spectrum disorders. FXS patients exhibit severe syndromic features and behavioral alterations, including anxiety, hyperactivity, impulsivity, and aggression, in addition to cognitive impairment and seizures. At present, there are no effective treatments or cures for FXS. Previously, we have found the divergence of BDNF-TrkB signaling trajectories is associated with spine defects in early postnatal developmental stages of Fmr1 KO mice. Here, young fragile X mice were intraperitoneal injection with 7,8-Dihydroxyflavone (7,8-DHF), a high affinity tropomyosin receptor kinase B (TrkB) agonist. 7,8-DHF ameliorated morphological abnormities in dendritic spine and synaptic structure and rescued synaptic and hippocampus-dependent cognitive dysfunction. These observed improvements of 7,8-DHF involved decreased protein levels of BDNF, p-TrkBY816, p-PLCγ, and p-CaMKII in the hippocampus. In addition, 7,8-DHF intervention in primary hippocampal neurons increased p-TrkBY816 and activated the PLCγ1-CaMKII signaling pathway, leading to improvement of neuronal morphology. This study is the first to account for early life synaptic impairments, neuronal morphological, and cognitive delays in FXS in response to the abnormal BDNF-TrkB pathway. Present studies provide novel evidences about the effective early intervention in FXS mice at developmental stages and a strategy to produce powerful impacts on neural development, synaptic plasticity, and behaviors.

Early environmental enrichment for autism spectrum disorder Fmr1 mice models has positive behavioral and molecular effects.

Autism spectrum disorder is a complex neurodevelopmental condition with genetic and phenotypic heterogeneity characterized by hallmark impairments in social functioning and repetitive behaviors. Fragile X syndrome (FXS), the leading single-gene form of autism spectrum disorder, is the most common form of inherited intellectual disability. Environmental enrichment has been shown to improve several aspects of brain development and affect histopathological, cognitive, and behavioral outcomes. However, the optimal time window to initiate it and improve cognitive and emotional development is largely unexplored. In the current study, we determined the longitudinal trends of BDNF-TrkB expression and dendritic development in FXS mice. Additionally, FXS mice were housed in an enriched environment when they showed significantly different BDNF-TrkB pathways and the phenotype of dendritic spines on postnatal day 10 (P10) until P60. The environmental enrichment delayed and attenuated some neurological alterations in FXS mice and prevented the development of cognitive and anxiety-related abnormalities and repetitive stereotyped behaviors. The correlation between neurotrophin-related pathways and multiple autistic-like behaviors was confirmed. Transcriptional profiling indicates that environmental enrichment increases the differences in the prefrontal cortex and hippocampal gene expression associated with the neural system and behavioral development. Our results provide novel evidence on the usefulness of early intervention for neurodevelopmental disorders as a strategy to facilitate positive effects on neural development and behaviors by acting on the BDNF/TrkB-PLCγ1-CaMKII pathway.

Calsyntenin-1 Negatively Regulates ICAM5 Accumulation in Postsynaptic Membrane and Influences Dendritic Spine Maturation in a Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is a neurodevelopmental disorder that causes intellectual disability, as well as the leading monogenic cause of autism spectrum disorders (ASD), in which neurons show aberrant dendritic spine structure. The reduction/absence of the functional FMRP protein, coded by the X-linked Fmr1 gene in humans, is responsible for the syndrome. Targets of FMRP, CLSTN1, and ICAM5, play critical roles in the maturation of dendritic spines, synapse formation and synaptic plasticity. However, the implication of CLSTN1 and ICAM5 in dendritic spine abnormalities and the underlying neuropathologic processes in FXS remain uninvestigated. In this study, we demonstrated that CLSTN1 co-localizes and co-transports with ICAM5 in cultured cortical neurons. Also we showed that shRNA-mediated downregulation of CLSTN1 in cultured WT neurons increases ICAM5 on the surface of synaptic membrane, subsequently affecting the maturation of dendritic spines. Whereas, normalization of CLSTN1 level in Fmr1 KO neurons reduces ICAM5 abundance and rescues impaired dendritic spine phenotypes. Most importantly, CLSTN1 protein is reduced in the postnatal medial prefrontal cortex of Fmr1 KO mice, which is correlated with increased ICAM5 levels on the surface of synapses and excessive filopodia-like spines. In conclusion, this study demonstrates that CLSTN1 plays a critical role in dendritic spine formation and maturation in FXS by regulating ICAM5 redistribution.